CN108186578A - A kind of preparation method of Ritonavir solid dispersions - Google Patents
A kind of preparation method of Ritonavir solid dispersions Download PDFInfo
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- CN108186578A CN108186578A CN201810256134.8A CN201810256134A CN108186578A CN 108186578 A CN108186578 A CN 108186578A CN 201810256134 A CN201810256134 A CN 201810256134A CN 108186578 A CN108186578 A CN 108186578A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
Abstract
The invention discloses a kind of preparation method of Ritonavir solid dispersions, the solid dispersions are prepared by Ritonavir as active component, polymer carrier copolyvidone VA64 and variety classes plasticizer.The solid dispersions are made by membrane process and torching mark, and Ritonavir is present in unformed shape in solid dispersions, significantly improve the dissolution rate and bioavilability of Ritonavir, solve the problems, such as that insoluble drug Ritonavir bioavilability is low.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of preparation method of Ritonavir solid dispersions.
Background technology
Ritonavir is human immunodeficiency virus -1（HIV-1）With human immunodeficiency virus -2（HIV-2）Aspartic acid egg
Oral effective inhibitor of white enzyme, its chemical name is N- [(2S, 3S, 5R) -3- hydroxyls -5- [[(2S) -3- methyl -2- [[first
Base-[(2- isopropyl -1,3- thiazole-4-yls) methyl] carbamyl] amino] butyryl] amino] -1,6- diphenyl-hex- 2- yls]
Carbamic acid 5- benzothiazolylmethyl esters, chemical structural formula are as follows：
Aspartic protease is the key enzyme of HIV particle maturations, and Ritonavir can inhibit the activity of the protease, block HIV
The duplication of virus, so as to prevent the sprawling of inhibition of HIV in vivo.Since Ritonavir is effective inhibitor of CYP3A liver enzymes, energy
Inhibit the bioconversion of CYP3A mediations, therefore the drug that clinically can be used alone or be combined other antiretroviral is used for
The treatment of AIDS patients.
This product arrives brown powder, molecular formula C for white37H48N6O5S2, relative molecular mass 720.95, fusing point is
It is 120-122 DEG C, water-soluble extremely low, the II class medicines of BCS that solubility is low, permeability is high are belonged in Biopharmaceutics Classification system
Object, dissolution rate are the rate-limiting steps of its bioavilability, and for this kind of drug, it is to improve its bioavilability to improve dissolution rate
Effective ways.
The common method for improving insoluble drug bioavilability includes reducing grain size, into salt, eutectic, solid dispersions
Deng.Solid dispersions are to improve insoluble drug solubility and the common technological means of bioavilability.Solid dispersions refer to by
The system that crystal form drug is highly dispersed in carrier and is formed, including following several types：（1）Crystal form solid dispersions.Drug
It is scattered in unformed carrier with crystal form state, existed in the form of two-phase；The glass transition temperature of drug can be still detected
It arrives；For dynamic stabilization system.（2）Glassy solids dispersion.The drug of melting is still deposited with unformed carrier in the form of two-phase
；It is intended to Mechanical instability, is easy to recrystallize under certain conditions.（3）Molecular state solid dispersions.Drug is with molecularity
State is scattered in polymer substrate, and diameter of aspirin particle reduces, and dissolution rate improves, and is Mechanical instability system.
The common method for preparing solid dispersions mainly has ball-milling method, solvent-fusion method, spray drying process, overcritical
CO2Extraction and hot-melt extruded method etc., and HME is compared with traditional preparation technique, there are many apparent advantages：Do not need to be organic
Solvent, continuous operation are easy to be scaled up to produce, do not need to downstream process and such as compress, become solid pharmaceutical preparation
One not interchangeable technology platform.
It, at least should there are a kind of auxiliary material and a kind of drugs during hot-melt extruded.Ideal mixing refer to two kinds or
Many kinds of substance is mixed by the even action of screw rod.The each region that is blended in melting process is all uniform, and mixed
There should not be any group of point of degradation in journey.It is combined by reducing grain size（Solid or sphere are shredded into smaller substance）And
Dispersion（The rearrangement of solid or melt）It realizes.The essence of hot-melt extruded process is that active constituents of medicine is constantly dispersed in load
In body matrix, selected carrier need to meet the requirement of some aspects such as glass transition temperature, thermal stability, hygroscopicity etc..
For the operating condition being optimal, adjuvant such as plasticizer, solubilizer etc. are usually added in the mixture.In short, HME be by
Drug, polymer and additive are added to by loading hopper in temperature control machine barrel, under the push of the screw element in machine barrel constantly
Forward becomes molten state, while under the action of hybrid element, shearing elements, the grain size for adding in material is continuous in particular section
Reduce, mixing is more uniform, is finally squeezed out with certain pressure, speed and shape from head die mouth.
1880s, BASF are earliest to apply torching mark in one of company of pharmaceuticals industry.This
Afterwards, HME has obtained large-scale promotion and application in medicament research and development and production.HME can improve the biology of medicinal active ingredient
Availability creates new medicine sustained and controlled release transmission system and carries out taste masking etc. to the tablet of bitter, has been applied to more and more
Research field.
A large amount of research, which is proved solid dispersions prepared by melt extrusion technology, can improve the solubility of insoluble drug.
As in recent years, have document report HME as a kind of selectable technology to solve that new drug molecule occurs in the formulation asks
Topic, such as Huang are built using Soluplus as carrier, are prepared for probucol-Soluplus solid dispersions, dissolution rate is reachable
To 97%, differential scanning calorimetry and X- powder diffractions show to be scattered in probucol in solid dispersions mainly with molecular state
In the presence of；Maddineni etc. research shows that, utilize HME technologies prepare Nimodipine-Kollidon VA64 solid dispersions carry
Dose can reach 40%, hence it is evident that improves the dissolution rate of drug, greatly improves the stability of solid dispersions.
In addition, in the market there are many drug prepared using torching mark, if Pfizer is with hydrochloric acid Wella pa
Rice is bulk pharmaceutical chemicals, with hydroxypropyl cellulose（HPC）Treatment hypertension and the anginal oral tablet prepared for carrier-
Covera-HS；Pedinol companies are using griseofulvin as bulk pharmaceutical chemicals, with polyethylene glycol（PEG）The treatment fungi sense prepared for carrier
Oral tablet-the Gris-PEG of dye；Merck companies are using posaconazole as bulk pharmaceutical chemicals, with acetic acid hypromellose succinic acid
Ester（HPMCAS）Oral tablet-the Noxafil for the treatment of invasive infections with fungi prepared for carrier；Abbott is with Ritonavir
For bulk pharmaceutical chemicals, with polyvinylpyrrolidone（PVP）Oral tablet-Norvir for treatment HIV infection prepared by carrier.
Invention content
The main object of the present invention is to provide a kind of solid dispersions of Ritonavir, exists so as to greatly improve Ritonavir
Stripping quantity in slightly solubility medium, and then improve its bioavilability and ensure its stability, to ensure drug effect.
The present invention provides a kind of preparation methods of Ritonavir solid dispersions, include the following steps：Place is weighed respectively
Ritonavir bulk pharmaceutical chemicals, polymer carrier copolyvidone VA64 and the variety classes plasticizer just measured, after being ground
Prepare Ritonavir solid dispersions.
The solid dispersions are prepared by following components in percentage by weight：Ritonavir 5%-20%, copolyvidone
VA64 75%-95%, plasticizer 0-8.3%.
One or two kinds of combinations of the plasticizer for following substance：Span 20（Span20）, PEG-6000, dioleoyl phosphorus
Phosphatidylcholine（DOPC）, dipalmitoylphosphatidylcholine（DPPC）, modified Fabaceous Lecithin（MSPC）, egg yolk lecithin（EPC）.
The method for preparing solid dispersions is membrane process or hot-melt extruded method.
It is described solid dispersions are prepared with membrane process to include the following steps：The object of Ritonavir, carrier material and plasticizer
Reason mixture is dissolved in suitable dichloromethane, and vortex 5min is placed in being completely dissolved in vacuum drying chamber, and 40 DEG C are dried under reduced pressure
20 min, dried object grind sieving to get the solid dispersions.
It is described solid dispersions are prepared with hot-melt extruded method to include the following steps：Ritonavir, carrier material and plasticizer
Physical mixture add in twin screw hot melt extruder, the temperature setting of twin screw hot melt extruder is 100 DEG C -130 DEG C,
The screw speed of hot-melt extruded machine is 20-40 rpm/min, is pulverized and sieved after extrudate cooling to get the solid dispersion
Body.
The Ritonavir solid dispersions are more suitable as 20 rpm/min using the screw speed of hot-melt extruded machine.
The solid dispersions of the preparation smash it through 80 mesh sieve.
Compared with prior art, the features of the present invention and advantageous effect are：
1. Ritonavir solid dispersions solid pharmaceutical preparation provided by the invention, Ritonavir is with crystallite state, unformed shape, colloid
Dispersed or molecule dispersed are present in carrier material, have very big dispersion degree, and the dissolution rate of drug is accelerated, can be promoted
Into the absorption of drug, bioavilability is improved；
2. the plasticizer Span20 that the present invention is applied is significantly improved in guarantee solid dispersions Fast Stripping, bioavilability
While, Ritonavir drug and the temperature of carrier material copolyvidone VA64 coextrusion can be effectively reduced, improves solid point
The stability of granular media reduces production cost and energy consumption.
Description of the drawings
Fig. 1 is the stripping curve of Ritonavir solid dispersions under different prescriptions prepared by membrane process.
The stripping curve of Ritonavir solid dispersions under different prescriptions prepared by Fig. 2 hot-melt extrudeds method, wherein (A)
RTV-VA64 SDs；(B) RTV-VA64/Span20 SDs；(C) RTV-VA64/MSPC SDs.
Ritonavir solid dispersions, Ritonavir bulk pharmaceutical chemicals, physics mix under different prescriptions prepared by Fig. 3 hot-melt extrudeds method
Close object, DSC collection of illustrative plates.(A) RTV-VA64 SDs；(B) RTV-VA64/Span20 SDs；(C) RTV-VA64/MSPC
SDs.a：Ritonavir bulk pharmaceutical chemicals；b：Physical mixture；c-e：The Ritonavir solid dispersions squeezed out under different temperatures.
Ritonavir solid dispersions, Ritonavir bulk pharmaceutical chemicals, physics mix under different prescriptions prepared by Fig. 4 hot-melt extrudeds method
Close object, XRD spectrum, wherein (A) RTV-VA64 SDs；(B) RTV-VA64/Span20 SDs；(C) RTV-VA64/MSPC
SDs.a：Ritonavir bulk pharmaceutical chemicals；b：Physical mixture；c-e：The Ritonavir solid dispersions squeezed out under different temperatures.
The SEM of Ritonavir solid dispersions and Ritonavir bulk pharmaceutical chemicals under different prescriptions prepared by Fig. 5 hot-melt extrudeds method
Collection of illustrative plates, wherein (a) RTV；(b) RTV-VA64 SDs（130 DEG C of extrusions）；(c) RTV-VA64/Span20 SDs（120 DEG C are squeezed
Go out）；(d) RTV-VA64/MSPC SDs（110 DEG C of extrusions）.
Ritonavir solid dispersions and Ritonavir bulk pharmaceutical chemicals 6 months under different prescriptions prepared by Fig. 6 hot-melt extrudeds method
DSC collection of illustrative plates afterwards, wherein (a) RTV；(b) RTV-VA64 SDs（130 DEG C of extrusions）；(c) RTV-VA64/Span20 SDs
（120 DEG C of extrusions）；(d) RTV-VA64/MSPC SDs（110 DEG C of extrusions）.
Ritonavir solid dispersions RTV-VA64/Span20 SDs prepared by Fig. 7 hot-melt extrudeds method（120 DEG C of extrusions）And
Medicine moving curve in rat body after Ritonavir bulk pharmaceutical chemicals RTV gastric infusions.
Specific embodiment
Below in conjunction with the drawings and specific embodiments, the invention will be further described.It should be noted that the description below
Merely to explaining the present invention, its content is not defined.Unless otherwise instructed, the content of following each ingredients used is attached most importance to
Measure degree.
The measure of 1 dissolution rate of embodiment：In the embodiment of the present invention to the measure of Ritonavir dissolution rate be according to China
What dissolution method paddle method as defined in pharmacopeia version in 2015 measured, dissolution medium is water or 0.1N hydrochloric acid (900 mL), is turned
Speed is 100 rpm, is sampled in 5,10,15,30,45,60 min, after filtering, is measured with high performance liquid chromatography, calculate each time
Point accumulation dissolution rate, draws stripping curve.
2 differential scanning calorimetric analysis of embodiment：The sample for weighing 4 mg is placed in aluminium dish, using aluminium oxide as reference substance,
Temperature elevating range is 25 DEG C~150 DEG C in nitrogen stream, with the rate heating scan of 10 DEG C/min.
3 X-ray diffraction of embodiment is analyzed：The sample for taking 10 mg is appropriate, is placed on the dedicated glass slide of powder diffraction,
The scanning angle of X-ray is 5 ° -40 °, and sweep speed is 5 °/min.
Embodiment 4 is by Ritonavir（16.7%）And copolyvidone VA64（83.3%）Physical mixture be dissolved in it is suitable
In dichloromethane, 5 min that are vortexed are placed in being completely dissolved in vacuum drying chamber, and 40 DEG C are dried under reduced pressure 20 min, dried object grinding
It pulverizes and sieves to get the RTV-VA64 SDs solid dispersions.
Embodiment 5 is by Ritonavir（16.7%）, copolyvidone VA64（75%）And variety classes plasticizer（8.3%）Object
Reason mixture is dissolved in suitable dichloromethane, and 5 min that are vortexed are placed in being completely dissolved in vacuum drying chamber, and 40 DEG C of decompressions are dry
Dry 20 min, dried object grind Ritonavir solid dispersions of the sieving to get the plasticizer containing variety classes.
Experimental result is shown in Fig. 1 for Ritonavir solid dispersions dissolution prepared by embodiment 4 and embodiment 5, can from Fig. 1
Go out, with Span20 and modified Fabaceous Lecithin（MSPC）When being added in solid dispersions prescription as plasticizer, Ritonavir is consolidated
The solubility of body dispersion in water has facilitation.
Embodiment 6 is by Ritonavir（16.7%）, copolyvidone VA64（83.3%）Physical mixture add in twin-screw heat
In molten extruder, the temperature setting of twin screw hot melt extruder is 110 DEG C, 120 DEG C, 130 DEG C, the screw speed of hot-melt extruded machine
For 20 rpm/min, pulverize and sieve after extrudate cooling to get the solid dispersions.
Embodiment 7 is by Ritonavir（16.7%）, copolyvidone VA64（75%）And span 20（8.3%）Physical mixture
It adds in twin screw hot melt extruder, the temperature setting of twin screw hot melt extruder is 100 DEG C, 110 DEG C, 120 DEG C, and hot melt squeezes
The screw speed for going out machine is 20 rpm/min, is pulverized and sieved after extrudate cooling to get the solid dispersions.
Embodiment 8 is by Ritonavir（16.7%）, copolyvidone VA64（75%）And modified Fabaceous Lecithin（8.3%）Physics mix
It closes object to add in twin screw hot melt extruder, the temperature setting of twin screw hot melt extruder is 110 DEG C, 120 DEG C, 130 DEG C, hot melt
The screw speed of extruder is 20 rpm/min, is pulverized and sieved after extrudate cooling to get the solid dispersions.
The dissolution result of Ritonavir solid dispersions prepared by embodiment 6,7,8 as shown in Figure 2, from Fig. 2 (A)
The dissolution result of RTV-VA64 SDs can be seen that prepared under different extrusion temperatures RTV-VA64 SDs dissolution situation difference compared with
Greatly, it is basic to be presented 130 DEG C>120℃>110 DEG C of trend, wherein the RTV-VA64 SDs prepared under 130 DEG C of extrusion temperatures
It can be dissolved out completely in 15min, dissolution rate is up to more than 90%.From the dissolution result of Fig. 2 (B) RTV-VA64/Span20 SDs
As can be seen that the RTV-VA64/Span20 SDs dissolution situation difference unobvious prepared under different extrusion temperatures, and prolong at any time
Long, whole that certain crystallization is presented, dissolution rate is presented 120 DEG C substantially>110℃>100 DEG C of trend, wherein 120 DEG C of extrusions
At a temperature of can dissolve out completely in the RTV-VA64/Span20 SDs 25min that prepare, dissolution rate is up to more than 80%.From Fig. 2 (C)
The dissolution result of RTV-VA64/MSPC SDs can be seen that the RTV-VA64/MSPC SDs dissolutions prepared under different extrusion temperatures
The similary difference of situation is larger, and with first two solid dispersions on the contrary, dissolution rate is presented 110 DEG C substantially>120℃>130 DEG C become
Gesture, wherein dissolution rate is i.e. up to more than 80% in the RTV-VA64 SDs 5min prepared under 110 DEG C of extrusion temperatures.It follows that
Using the extrusion temperature being modified during Fabaceous Lecithin can not only reduce hot-melt extruded as Ritonavir solid dispersions prepared by plasticizer
Degree reduces energy consumption, and can realize the purpose that Ritonavir bioavilability significantly improves.
The DSC collection of illustrative plates and XRD spectrum of Ritonavir solid dispersions prepared by embodiment 6,7,8 are shown in Fig. 3 and Fig. 4 respectively
It is shown, from the DSC collection of illustrative plates and XRD spectrum, Fig. 3 (B) and Fig. 4 (B) RTV-VA64/ of Fig. 3 (A) and Fig. 4 (A) RTV-VA64 SDs
The DSC collection of illustrative plates and XRD spectrum and Fig. 3 (C) of Span20 SDs and the DSC collection of illustrative plates and XRD of Fig. 4 (C) RTV-VA64/MSPC SDs
Collection of illustrative plates can be seen that is squeezed out under different temperatures, and in the Ritonavir solid dispersions under different prescriptions, Ritonavir is with nothing
Amorphous form exists, favorable dispersibility.
Ritonavir solid dispersions RTV-VA64 SDs prepared by embodiment 6,7,8（130 DEG C of extrusions）、RTV-
VA64/Span20 SDs（120 DEG C of extrusions）、RTV-VA64/MSPC SDs（110 DEG C of extrusions）And the SEM photograph of RTV active compounds is shown in figure
Shown in 5, RTV active compounds are can be seen that as rodlike crystallization from the SEM photograph of Fig. 5 (a) RTV active compounds, form is clear, Fig. 5 (b)
RTV-VA64 SDs, Fig. 5 (c) RTV-VA64/Span20 SDs and Fig. 5 (d) RTV-VA64/MSPC SDs SEM spectrum in
The rodlike crystalline texture of RTV active compounds disappears, RTV with micro crystal or it is unformed it is homodisperse in the carrier, solid dispersions knot
Structure is fine and close, more consistent with DSC and XRD results.
Ritonavir solid dispersions RTV-VA64 SDs prepared by embodiment 6,7,8（130 DEG C of extrusions）、RTV-
VA64/Span20 SDs（120 DEG C of extrusions）And RTV-VA64/MSPC SDs（110 DEG C of extrusions）DSC collection of illustrative plates after 6 months is shown in Fig. 6
It is shown, from Fig. 6 (a) RTV active compounds, Fig. 6 (b) RTV-VA64 SDs, Fig. 6 (c) RTV-VA64/Span20 SDs and Fig. 6 (d)
The DSC curve of RTV-VA64/MSPC SDs can be seen that RTV solid dispersions and have good stability, and be placed at room temperature for half a year, solid
The crystallization of RTV active compounds is had no in dispersion to occur.Before and after comparing placement 6 months, the drugloading rate variation of three kinds of solid dispersions, as a result
It has been shown that, RTV-VA64 SDs, RTV-VA64/Span20 SDs and tri- kinds of solid dispersions drugloading rates of RTV-VA64/MSPC SDs
14.4%, 2.5% and 20.3% is reduced respectively, is reduced with RTV-VA64/Span20 SDs drugloading rates minimum.Therefore, in contrast,
It is best with the RTV-VA64/Span20 SDs stability containing 8.3% Span20.
Ritonavir solid dispersions RTV-VA64/Span20 SDs prepared by embodiment 7（120 DEG C of extrusions）And active compound
RTV single doses（8 mg/kg）After gastric infusion, medicine moving curve in rat body is as shown in fig. 7, from figure 7 it can be seen that and Li Tuona
Wei bulk pharmaceutical chemicals are compared, and RTV-VA64/Span20 SDs bioavilabilities significantly improve.Software processing, RTV are moved through Pksolver medicines
The peak time of bulk pharmaceutical chemicals and RTV-VA64/Span20 SDs（tmax）Respectively 1 h and 15 min；Up to Cmax（Cmax）Respectively
For 0.144 mg/L and 0.199 mg/L；Half-life period（T1/2）Respectively 4.338 h and 7.409 h；Area under the drug-time curve
AUC0-tRespectively 1.986 mgh/L and 2.042 mgh/L；AUC0-∞Respectively 2.800 mgh/L and 2.942 mg
h/L；Internal mean residence time（MRT）Respectively 6.260 h and 10.691 h；Internal clearance rate（CL）Respectively 0.571 L/
H and 0.544 L/h.Statistic analysis result shows compared with RTV active compounds, RTV-VA64/Span20 SDs Increased Plasma Half-lifes
1.71 again；Increase 1.38 times up to Cmax；AUC0-t1.03 times are improved, AUC0-∞Improve 1.05 times；During internal Mean Residence
Between extend 1.71 times；Internal clearance rate is decreased to original 95%, it can be considered that Ritonavir solid dispersions RTV-
VA64/Span20 SDs can significantly improve the bioavilability of Ritonavir, this is also more consistent with dissolution result.
Claims (10)
1. a kind of preparation method of Ritonavir solid dispersions, which is characterized in that include the following steps：Recipe quantity is weighed respectively
Ritonavir bulk pharmaceutical chemicals, polymer carrier copolyvidone VA64 and variety classes plasticizer, prepared after being ground
Ritonavir solid dispersions.
2. preparation method according to claim 1, which is characterized in that the solid dispersions are by following weight percent
Component is prepared：Ritonavir 5%-20%, copolyvidone VA64 75%-95%, plasticizer 0-8.3%.
3. preparation method according to claim 2, which is characterized in that Ritonavir 16.7%, polymer carrier
83.3%。
4. preparation method according to claim 2, which is characterized in that Ritonavir 16.7%, polymer carrier 75%,
Plasticizer 8.3%.
5. preparation method according to claim 2, which is characterized in that the plasticizer is the one or two of following substance
Combination：Span 20（Span20）, PEG-6000, Dioleoyl Phosphatidylcholine（DOPC）, dipalmitoylphosphatidylcholine（DPPC）、
Modified Fabaceous Lecithin（MSPC）, egg yolk lecithin（EPC）.
6. preparation method according to claim 1, which is characterized in that the method for preparing solid dispersions is membrane process or heat
Molten extrusion molding.
7. preparation method according to claim 1, which is characterized in that solid dispersions are prepared with membrane process and include following step
Suddenly：The physical mixture of Ritonavir, carrier material and plasticizer is dissolved in suitable dichloromethane, vortex 5min to completely it is molten
Solution, is placed in vacuum drying chamber, and 40 °C are dried under reduced pressure 20 min, and dried object grinds sieving to be disperseed to get the solid
Body.
8. preparation method according to claim 1, which is characterized in that with hot-melt extruded method prepare solid dispersions include with
Lower step：The physical mixture of Ritonavir, carrier material and plasticizer is added in twin screw hot melt extruder, certain temperature and
It squeezes out under rotating speed, pulverizes and sieves after extrudate cooling to get the solid dispersions.
9. preparation method according to claim 8, which is characterized in that the temperature setting of twin screw hot melt extruder is 100
°C -130 °C, the screw speed of hot-melt extruded machine is 20-40 rpm/min（It is preferred that the screw speed of hot-melt extruded machine is 20
rpm/min）.
10. preparation method according to claim 1, which is characterized in that the solid dispersions of preparation smash it through 80 mesh sieve.
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| CN110354081A (en) * | 2019-08-01 | 2019-10-22 | 聊城高新生物技术有限公司 | The preparation method for the Ritonavir solid dispersions being precipitated in an aqueous medium can be reduced |
| CN112336691A (en) * | 2020-10-22 | 2021-02-09 | 安徽贝克生物制药有限公司 | Ritonavir tablet and preparation method thereof |
| CN113318076A (en) * | 2021-06-02 | 2021-08-31 | 聊城大学 | Ritonavir solid dispersion with solubilizing and crystal inhibiting effects and preparation method thereof |
| CN114557967A (en) * | 2022-03-17 | 2022-05-31 | 乐普制药科技有限公司 | Preparation method of ritonavir solid dispersion |
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